The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to WTC aerosolized dust and gases that contained known and suspected carcinogens including polycyclic aromatic hydrocarbons, polychlorinated biphenyls, polychlorinated furans, dioxins and asbestos. In our sentinel study of cancer incidence following WTC exposure, we reported a modest excess of cancer cases in the WTC-exposed Fire Department of the City of New York (FDNY) firefighters compared with US population rates and rates in non-WTC-exposed firefighters despite a relatively short follow up period of 7 years (Zeig- Owens et al, Lancet, 2011)(1). Longer follow up of WTC exposed firefighters revealed a trend towards higher incidence of multiple myeloma and leukemias in these cases. We continue to prospectively follow the entire FDNY cohort of firefighters for cancer incidence and have built a biorepository of samples consisting of fractionated blood components and serum from 3000+ WTC exposed FDNY subjects and non WTC exposed firefighter controls. Using this cohort we have conducted preliminary studies in 781 WTC exposed firefighters that demonstrate a significantly higher prevalence of monoclonal gammopathy (MGUS), a precursor for multiple myeloma. Interestingly, we observed a higher rate of light chain disease that is specifically linked to chronic immune stimulation. Furthermore, we have conducted genome sequencing of a cohort of WTC exposed firefighters revealing a higher incidence of genomic instability in these cases and suggesting potential risk for development of myeloid neoplasms such as myelodysplastic syndromes (MDS). Based on these data, we now propose to comprehensively determine the prevalence of hematologic malignancies and premalignant conditions in WTC exposed firefighters. Aim 1 will determine the prevalence of myeloma and its precursor state, monoclonal gammopathy of unknown significance (MGUS) by use of serum proteomic analyses. Aim 2 will determine the prevalence of chronic lymphocytic leukemia (CLL) and its precursor lesions in this cohort. CLL is associated with environmental exposures and we have shown that CLL is preceded by a monoclonal B- cell lymphocytosis (MBL) that can be detected by flow cytometry (Landgren et al, NEJM, 2009)(2). Cryopreserved mononuclear cells from WTC exposed firefighters will be examined for presence of MBL/CLL and specific immunoglobulin chain rearrangements. Aim 3 will determine the prevalence of MDS by evaluation of mutations using next generation sequencing. Myelodysplasia is a preleukemic neoplasm that is associated with genotoxic exposures. Based on our preliminary data demonstrating increased single nucleotide variants in WTC?exposed firefighter samples, we propose to conduct deep sequencing to detect MDS/myeloid leukemia associated mutations in a cohort of firefighter and control samples. Early detection of hematologic malignancies would enable potentially disease altering therapeutic interventions for most of these cancers, which are often incurable when detected at late stages.